X-chromosome inactivation is surprisingly found in various types of cancer in men

X-chromosome inactivation is surprisingly found in various types of cancer in men

Cancer cells acquire genetic changes that allow them to grow and proliferate without control. Researchers at the Dana-Faber Cancer Institute and their colleagues have now found another difference between cancer cells and normal cells. The team analyzed public data sets comprising thousands of cancer DNA samples. Their results showed that X chromosome inactivation (chrX) (XCI), the process by which one of the two X chromosomes in female cells (XX) is inactivated, can also occur in male cancers. High expression of XIST, the gene responsible for shutting down gene expression on the X chromosome, was found in approximately 4% of male cancer samples tested. The researchers suggest that future research may ultimately point to new therapeutic targets.

Srinivas Viswanathan, MD, PhD, a cancer geneticist and medical oncologist at the Dana-Farber Cancer Institute, is the lead author of the paper published by the team in cellular systemstitled, “Somatic activation of XIST and features of X chromosome inactivation in male human cancers.”

Expression of the non-coding RNA XIST is essential for initiating X-chromosome inactivation during early development in mammalian females, the authors noted. “In normal women, XIST expression serves to achieve dose compensation between the sexes by silencing one of the two copies of chrX.” Although XIST is generally considered a female-only transcript, it is also found in males in germ cells and in individuals with supernumerary X chromosomes. Viswanathan explained: “To balance gene expression between the sexes, in normal development, one copy of the female X chromosome is randomly inactivated throughout the human body.

Although XIST can be expressed very early in development in all sexes, inactivation of X is thought to be a female-specific process later in development. It has also been previously shown that some female cancer cells may lose the ability to inactivate one of their X chromosomes, leading to increased expression of X-linked genes. X inactivation has still been studied primarily in female cells.

The authors set out to investigate whether XCI can also occur in cancer cells. “We wanted to know if this process that occurs in normal development goes awry in genetically unstable male or female cancer cells,” Viswanathan said.

Graphic summary representing the workflow of the study. [Cell Systems/Sadagopan et al.]

Through their analysis of publicly available datasets comprising thousands of DNA samples from cancer patients worldwide, the researchers identified XIST expression in approximately 4% of male cancer samples, as well as loss XIST expression in some female cancers. “Together, our analysis of multiple cancer datasets suggests XIST dysregulation, including its expression in male cancers and its loss in female cancers, as a low-frequency but recurrent feature of human cancers,” they wrote.

Within the 4% of abnormal male cancer samples identified, 74% were from reproductive cancers that had already been shown to inactivate the X chromosome, but that left 26% of samples from other cancers. These included cancers of the liver, brain, skin, heart, lung, and thyroid. “Our results reveal that XIST is expressed and active in a broad spectrum of male cancers,” the researchers stated. “Some of these cancers show features of XCI, including silencing of gene expression, reduced chromatin accessibility, and increased DNA methylation on the X chromosome, suggesting that the XCI program can be accessed somatically. Female-specific and developmentally restricted XCI in male cancers”.

“We were very surprised by this result, as XIST is a transcript that is typically used to classify female cancers, so we wanted to make sure this was not simply the result of incorrect annotation. However, we do see that some male cancers of various subtypes activate XIST and show X-inactivating features,” said Viswanathan.

“We have to be aware of the caveats of working with these kinds of data sets. These samples have been in the hands of many people, and there is more room for human error,” said co-corresponding author Cheng-Zhong Zhang, PhD, a cancer biologist at Dana-Farber Cancer Institute. “This is the biggest source of uncertainty for us; we have to be creative in the way we look at the data and find controls.”

One possible explanation for why this phenomenon occurs is genetic instability. Cancers often have multiple copies of chromosomes, and if two X chromosomes are in a cell, then it may be necessary to inactivate one of them by activating XIST, regardless of whether that cell is in a male or female individual.

“Another possibility is that there are some important genes on the X chromosome that, when silenced, allow the cancer to grow. We will investigate this in future studies,” said Viswanathan. “In some ways, sex is the ultimate biomarker in that it subdivides the human population, but we often don’t think about how genetic differences between the sexes can inform cancer prognosis or response to therapy.”

In their report, the researchers concluded: “Further studies of the signals that induce XIST expression in certain cancer types, the differences between physiological and cancer-related XCI, and the functional consequences for cancer cell fitness may illuminate.” potential targets for therapeutic intervention. ”

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